with preexisting phenotypic differences.
Mu et al. used RNA-sequencing data sets
of clinical samples to identify transcription
factors whose expression correlated with
co-occurring alterations in the RB1 and
TP53 signaling pathways. Among these,
SOX2 expression was induced by silencing
RB1 and TP53 in LNCaP-AR cells, and SOX2
expression in these cells was necessary and
sufficient for the expression of basal epithelial and neuroendocrine markers as well as
for enzalutamide resistance. RB1 loss has
been associated with lineage plasticity in
other cancer cell models, and in induced
pluripotent stem cells, RB1 inhibited the
basal transcription of SOX2 and other pluripotency genes ( 8). These data suggest a
model whereby the induction of SOX2 expression subsequent to RB1 and TP53 loss
contributes to neuroendocrine differentiation and AR-pathway independence.

SOX2, an E2F-regulated gene, was identified as a downstream mediator of RB1-
dependent lineage plasticity. SOX2 plays
context-dependent roles in both maintaining pluripotency and driving neuronal progenitor differentiation ( 11). It will
be important to determine the various
roles for SOX2 and to what extent in vitro modeling can be generalized to disease
progression in vivo. Moreover, the effects
of EZH2 inhibition are a key finding and
parallel other studies showing the importance of EZH2-dependent mechanisms in
supporting CRPC-NE growth, including
models initiated by other drivers ( 12). Notably, EZH2 is also a direct AR coactivator
( 13). This suggests that EZH2 inhibition in
combination with other therapeutics, including enzalutamide, has the potential to
increase responses in patients with CRPC-NE disease. j

REFERENCES

1. P. Mu et al ., Science355, 84 (2017).

2. S. Y. Ku et al., Science 355, 78 (2017).

3. P.A. Watson, V.K.Arora, C.L.Sawyers, Nat. Rev. Cancer15,

701 (2015).

4. A.Aparicio,C.J.Logothetis, S.N.Maity, Cancer Discov. 1,

466 (2011).

5. J. H. E. Small et al ., J. Clin. Oncol. 33 (suppl.), abstr. 5003

(2015).

6. H. Beltran et al. , Nat. Med. 22, 298 (2016).

7. J. L. Bishop et al. , Cancer Discov. 7, 1 (2016).

8. M. S. Kareta et al., Cell Stem Cell 16, 39 (2015).

9. A.Kumaretal.,Nat.Med. 22,369(2016).

10. A.Sharma et al., J. Clin. Invest.120,4478(2010).

11. A. Sarkar, K. Hochedlinger, Cell Stem Cell 12, 15 (2013).

12. E. Dardenne et al., Cancer Cell 30, 563 (2016).

13. K. Xu et al. , Science 338, 1465 (2012).

10.1126/science.aam5355

Androgen-indiferent, AR+/_

After treatment with an AR antagonist, cells
with altered RB1 and TP53 are selected.

Factors including SOX2 and EZH2 contribute
to dediferentiation and plasticity.

Androgen-independent, AR_

Cells established are most often
reprogrammed to the neuroendocrine
lineage that is resistant to
enzalutamide.